Soft tissue substitute and method of soft tissue reformation

ABSTRACT

A soft tissue implant material is formed from biologically-compatible polymeric particles. The particles may have a diameter of up to about 500 microns and intraparticulate pores sized for ingrowth of soft tissue. The particles may have an inner core of a first biologically-compatible polymeric material and an outer layer generally surrounding the inner core, with the outer layer comprised of a second biologically-compatible polymeric material being hydrophilic and having a composition different from the composition of the first polymeric material. The material may be utilized with collagen or other matrix materials. This material may be used in a method of reforming soft tissues by implanting the material within soft body tissues to modify soft tissue defects such as wrinkles; or oral gingival tissue defects and reshape soft tissue, e.g., for urinary bladder inconvenience.

This application is a divisional of U.S. Ser. No. 09/448,692, filed Nov.24, 1999, now U.S. Pat. No. ______, issued ______, which is incorporatedherein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to reformation of soft tissues within thebody. More particularly, the invention relates to compositions useful inreforming the shape of soft tissues and methods of using suchcompositions in reforming soft tissues.

2. Description of Related Art

The medical community for many years has been attempting to developmaterials and techniques to replace tissues with the body. It may bedesirable to replace such tissue due to, for example, injury, disease,side effects of medical procedures and surgeries, and the aging process,for example. In addition, some patients may desire to alter theirappearance for cosmetic reasons, particularly the contour of visiblesoft tissues. Much attention has been given to the reformation of softtissue to locally increase its volume and change its shape.

To this end, numerous replacement materials have been tried, withcertain advantages and disadvantages. Silicone has been used fordecades, but can displace and harden over time. Plastic and metalimplants have also been used. However, implants such as these may nothave a “natural” look or feel, especially as the body changes over time.

Since the early 1980's, injectable collagen has been extensively used invarious procedures. Injectable collagen is either synthetic or natural,which is derived from reconstituted bovine collagen. Injectable collagenhas been used throughout the body tissues. It may be accuratelycontrolled in both placement and amount, and may have a more “natural”look and feel than other tissue substitutes.

The primary drawback of injectable collagen is its resorbable nature.Collagen quickly undergoes proteolytic degradation within the body,resulting in relatively short clinical effectiveness. Patients mustreceive additional injections to maintain tissue reformation, usually atan interval of about every few months. Continual submission to theinjection procedure causes the patient inconvenience, expense, andperhaps pain, discomfort, and other side effects. As with any invasivemedical procedure, injection carries with it the risk ofcross-contamination and infection. Moreover, as the collagen is resorbedby the body, the patient may suffer a return of the physicaldysfuinction the injection corrected, or experience undesirable andirregular changes in cosmetic appearance.

More recently, concern has arisen in the medical and veterinarycommunities regarding the transmission of tissue-born diseases amonganimal species and humans. For example, bovine spongiform encephalopathymay move from animals to humans and cause new variant Creutzfeld-Jacobdisease, which is fatal. Accordingly, some medical experts have searchedfor synthetic alternatives that reduce the use of animal-based tissues.

U.S. Pat. No. 4,536,158 issued to Bruins and Ashman discloses asynthetic porous implantable bony tissue replacement. A prosthesis isformed by bonding together a material composed of polymeric particles.

U.S. Pat. Nos. 4,535,485 and 4,547,390, issued to Ashman et al.,disclose a synthetic material and method for making hard tissuereplacement prostheses. That material is comprised of polymericparticles coated with a hydrophilic polymeric material. The particlesare of sufficient size to be packed into hard tissue areas of the body,and have pores between the particles of sufficient size for tissue,i.e., hard tissue, to grow into the pores and secure the prostheses.

U.S. Pat. No. 4,728,570 issued to Ashman et al. also discloses a hardtissue prosthesis material. That material comprises polymeric particlescoated with a hydrophilic polymeric material, with calcium hydroxidedistributed on the surfaces and within the material to induce hardtissue growth into the pores between the particles. The particles may bebonded together to form an implantable prosthesis or may be used as apacking material for forming a hard tissue prosthesis in vivo. Thematerial is sold by Bioplant, Inc. of South Norwalk, Conn., under thetrade name Bioplant® HTR®.

In U.S. Pat. Nos. 4,902,511 and 4,912,141 issued to Kronman, an implantfor fibrous or cartilaginous tissue is disclosed. A sponge-like implantis formed by polymerizing a hydrophilic polymeric material. The implantis shaped by either polymerizing it in a mold or shaping it by cuttingor grinding.

While several tissue substitute materials for bony, cartilaginous, andfibrous tissues exist, it would be desirable to have substitutematerials for soft tissues. It would also be desirable to have a softtissue replacement material that was non-resorbable, supple, flexible,and durable so that a patient would not have to undergo repeatedprocedures. Also, a replacement material that could be implanted inloose (particulate) form for in vivo integration that did not migratewould be highly desirable.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a soft tissuesubstitute.

It is another object of the invention to provide a soft tissuesubstitute that is at least partially non-resorbable, supple, flexibleand durable so that patients do not need to undergo repeated procedures.

Another object of the invention is to minimize patient discomfort, riskof infection and side effects of repeated medical procedures.

It is another object of this invention to provide a soft tissuesubstitute that may be implanted into the body in loose (particulate)form, that does not migrate.

It is a further object of this invention to provide a soft tissuesubstitute that is synthetic, bioinert and may contain naturalmaterials.

It is yet another object of the invention to provide a soft tissuesubstitute that may be used to reform and augment soft tissues,including soft tissue contour defects.

The present invention is a soft tissue implant material comprisingbiologically-compatible polymeric particles. The particles may have aporous surface. The particulate nature of the material provides anatural feel and is held by the body's existing tissue and tissue formedinto the pores and around and between the particles. The implantmaterial may be combined with a variety of matrix materials, includingcollagen. The volumetric ratio of particles to matrix material may bevaried depending on the application, i.e. the soft tissue intended to bereplaced. The particles may compose up to 100% of the volume of thematerial. The implant material may also contain bioactive substances,which may, for example, be grafted to the particles. The implantmaterial may be formed by known methods.

The invention also features methods for reforming and augmenting softtissues. The implant material may be implanted into soft tissue at adesired location. In injectable form it may be accurately placed withinsoft tissue using a syringe or orthoscopic device. In this manner, theimplant material may be used to correct soft tissue defects, (e.g. byplumping and expanding tissues) remediate medical conditions such asincontinence, and for cosmetic procedures.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features of the present invention will be morereadily apparent from the following detailed description and drawings ofan illustrative embodiment of the invention where like reference numbersrefer to similar elements throughout the several view and in which:

FIG. 1 shows a cross-sectional schematic of cutaneous soft tissue havinga contour defect;

FIG. 2 shows a cross-sectional schematic of the cutaneous tissue of FIG.1 after the implant material of the present invention has been implantedsubcutaneously; and

FIG. 3 shows a schematic of a portion of the human male urinary tractafter prostrate removal with constriction of the urethra after theimplant material of the present invention has been injected into thesphincter urethrae.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention features materials that may be implanted into softbody tissue for correction of soft tissue defects or for soft tissueaugmentation. The material comprises biologically-compatible polymericparticles, which have intraparticulate pores. The material may becombined with collagen or other matrix materials including, but notlimited to, blood, saline, sterile water or glucose. The matrix materialacts as a medium for particles and may help in the dispensing, e.g.,injection, of the material when first implanted. The use of matrixmaterials also allows the amount of soft tissue augmentation to be moreaccurately controlled. As matrix material is resorbed, additionalimplantation can be accomplished, as necessary. The volume of matrixmaterial in the implant material is preferably between about 30% and65%. Most preferably, the volume of is about 50%. However, one skilledin the art will appreciate how much matrix material to combine to obtaina particular desired result.

A combination of the particulate material and collagen has severaladvantages. First, collagen has a known consistency. Second, collagen isresorbable by the body, and is completely resorbed over a period of afew months. Synthetic particles are not resorbed, and may be permanentlyretained bioinertly within the tissue. Collagen has a natural look andfeel when injected for cosmetic applications, helping ensure the patientis satisfied with the outcome. Porous synthetic particles offer asimilar outcome.

In another embodiment of the invention, the implant material may becombined with adipose (fat) tissue. Fat tissue acts as a bulking agentthat helps to dispense and hold the implant material in place afterimplantation. Fat is also resorbable by the body, and when taken fromthe patient's own body, the risk of rejection of is significantlyreduced. As discussed herein, other embodiments of the invention mayutilize matrix materials to facilitate delivery of the material to theimplantation site.

In a further embodiment of the invention, the implant material maycontain bioactive substances. These substances can be therapeutic and,for example, promote tissue growth, i.e., growth factors, or act as anantimicrobial. These substances may also be grafted to or absorbed bythe particles, and may be of a nature so that they are time-released inthe surrounding tissue. Those skilled in the art will recognize thevarious bioactive substances that may be incorporated into the implantmaterial and their medical value, depending on the application.

Preferably, the polymeric particles have an hollow inner core, and anouter layer of a different, hydrophilic polymeric material such aspolymeric hydroxyethylmethacrylate (PHEMA), which preferably iscomprised of a copolymer of monomeric hydroxyethylmethacrylate and across-linking agent. Preferred cross-linking agents includetriethyleneglycol dimethacrylate, tetraethyleneglycol dimethacrylate,diethyleneglycol dimethacrylate, and monoethyleneglycol dimethacrylate.Cross-linking agents preferably comprise from about 0.1 percent to about5 percent by weight of monomeric hydroyethylmethacrylate. The inner coreis preferably an acrylic polymer, such as polymethylmethacrylate (PMMA).In another embodiment of the invention, calcium hydroxide coats theouter layer. Calcium hydroxide has an alkaline effect that may reduceacidic environments that have been associated with infection. Suitablematerial includes various formulation of Bioplant® HTR® available fromBioplant, Inc.

When this material is implanted into soft tissue, dense, fibrous andflexible tissue forms around and into the porous portion of thematerial. This occurs within a few days of implantation. The implantedmaterial remains inert within the body, and with the newly formedtissue, augments or shapes the soft tissue as desired.

The composition of the implant material determines the nature of thetissue formation. Generally, vascularization is undesirable with softtissue augmentation. Therefore, the particles are preferably about 500microns in diameter or less, preferably about 50 to about 200 microns.Larger particle sizes may result in interstices between particles thatare large enough to allow unwanted vascularization. In addition, growthof tissue into the implant material is dependent upon the presence andsize of pores in the particles. Ingrowth helps integrate and retain theimplant material in place. Preferably, the proportion of pores in thematerial is from about 0 percent to about 60 percent, with pore sizes ofless than about 100 microns. This allows sufficient retention of thematerial while maintaining a high proportion of augmenting particles.Most preferably, the proportion is from about 40 to about 60 percent,and pore sizes between about 50 and about 100 microns.

Preferred procedures for producing the polymeric particles for implantmaterials of the invention are disclosed in U.S. Pat. Nos. 4,535,485 and4,547,390, the specifications of which are incorporated herein byreference. In various embodiments of the present invention, theparticles may be of about 34 mesh size or smaller (particle diameters ofabout 500 microns or less). For embodiments of the invention containingcalcium hydroxide, preferred procedures for producing polymericparticles are disclosed in U.S. Pat. No. 4,728,570, which isincorporated herein by reference.

Combining the particulate material with the matrix material may beaccomplished by various methods, depending on the application. Inapplications where the implant site will be exposed, for example, theparticulate material and matrix material may be combined into a paste.In embodiments where the implant material is to be injected, theparticulate material may be placed in a syringe and the matrix materialdrawn into the syringe to “hydrate” the material. Those skilled in theart will appreciate these and other methods of preparing the implantmaterial.

The present invention also contemplates a method of soft tissueaugmentation. Soft-tissue implant materials of the invention areinexpensive to manufacture and may be used to advantage in many medical,dental, cosmetic, and veterinary applications. The material may beimplanted into specific tissues in the body to provide desiredaugmentation. Preferably, the material is combined with one or morematrix materials before implantation. Preferred matrix materials aresterile water, saline solution, collagen, blood and glucose. In orderfor there to be ample fluidity, the matrix material may comprise avolume of between about 30% and about 65%, and most preferredly about50%, of the implanted material. Those versed in the art will appreciatewhich and how much matrix material to use for a particular application.

In certain embodiments of the invention, the implant material isinjected, e.g., by syringe or orthoscopic devices. These methods arepreferred because they are less invasive than other, e.g., surgical,procedures, lessen the risk of infection, discomfort, and complications,and can be easily controlled in amount and location. For materialscontaining collagen, it is preferable that the collagen be in injectableform. One skilled in the art will know the various methods of injection.For example, embodiments of the invention having a particle size ofabout 500 microns may be injected using an 18-gauge syringe. Thoseembodiments having smaller particles may be injected with higher-gaugeneedles, e.g., orthoscopically.

In one embodiment of the invention, the implant material is injectedsubcutaneously into an area having a soft tissue contour defect. Theamount implanted is in a sufficient amount to at least partially,preferably entirely, remove the defect. Such defect may include, forexample, wrinkles.

Referring to the drawings, and initially to FIG. 1, skin 10 consists ofthe epidermis 11 and the dermis 12. The hypodermis 13, also called thesubcutaneous layer, contains collagen, elastic tissue, and adipose (fat)(not shown in any more detail). The hypodermis 13 provides underlyingstructure for the skin, and thus greatly contributes locally to itscontour 14. The hypodermis 13 may lose its adipose, collagen, andelastic tissue, especially as the skin 10 ages. This can result invacuities 15 in the hypodermis and loss of support for the overlayingdermis 12 and epidermis 11, i.e., the skin sags, forming wrinkles 16.

In FIG. 2, the implant material 20 of the present invention has beeninjected under the skin 10 into the hypodermis 13 beneath the dermis 12.The implant material 20 fills the vacuities 15, providing support forthe skin 10. The material 20 also pushes out the skin 10, causing it tohave a much smoother surface contour 21.

In another embodiment of the invention, the implant material may be usedto control incontinence. Such incontinence may be the result of disease,aging, or neuromuscular degeneration. It may also result from prostatesurgery that causes localized damage to the nerves controlling thesphincter surrounding the urethra. As shown in FIG. 3, the urethra 30 isconnected to the bladder 31. The sphincter urethrae 32 is attached tothe pelvis 33 and surrounds the urethra 30. The prostate 34 (shown inphantom) which surrounds the urethra 30 between the bladder 31 and thesphincter urethrae 32 is shown as having been previously removedsurgically. Often this surgery damages the controlling sphincterurethrae 32 or causes indirect flaccidity due to nerve damage. Where apatient has lost some or all control of the sphincter urethrae 32, hewill not be able to constrict the urethra 30 and prevent urine flow. Inthe present invention, implant material 35 is injected into thesphincter urethrae 32, swelling it, reshaping it, and causing at least apartial closure and constriction 36 of the urethra 30. Contraction ofother muscles, e.g., the abdominal muscles, in the area of the bladder(not shown) will push the sphincter 32 and allow urine to flow past theconstriction 36, even where there is no direct control over thesphincter.

Preferably, between about 2 cc and about 4 cc of implant material isinjected into the sphincter urethrae 32 to cause constriction 36 of theurethra 30. However, one skilled in the art will appreciate how muchimplant material to inject according to the particular medical conditionof the patient.

Those skilled in the art will recognize that the compositions andmethods of the present invention will have various other uses inaddition to the above described embodiments. They will appreciate thatthe foregoing specification and accompanying drawings are set forth byway of illustration and not limitation of the invention. It will furtherbe appreciated that various modifications and changes may be madetherein without departing from the spirit and scope of the presentinvention, which is to be limited solely by the scope of the appendedclaims.

1. A method of augmenting soft tissue comprising: a. providing abiologically compatible implant material comprised of at least partiallynon-resorbable biologically compatible polymeric particles havingcalcium hydroxide thereon, wherein said particles have intersticestherebetween with dimensions effective to permit soft tissue to growtherein; and b. implanting said implant material within soft tissue. 2.Method of claim 1 wherein said implanting step includes the step ofinjecting said implant material.
 3. Method of claim 2 wherein saidinjecting step includes injecting said implant material subcutaneouslyinto an area having a soft tissue contour defect in an amount sufficientto at least partially remove said defect.
 4. Method of claim 3 whereinsaid soft tissue contour defect comprises wrinkles.
 5. Method of claim 3wherein said soft tissue contour defect includes gingival soft tissuedefects in the mouth.
 6. Method of claim 2 wherein said injecting stepincludes injecting said material into the sphincter surrounding theurethra in an amount sufficient to at least partially constrict saidurethra.
 7. Method of claim 6 wherein said injecting step includesinjecting between about 2 cc and about 4 cc of said implant material. 8.Method of claim 1 wherein said particles have a diameter of up to about500 microns.
 9. Method of claim 8 wherein said particles have a diameterof about 50 to about 200 microns.
 10. Method of claim 1 wherein saidparticles have intraparticulate pores, said pores having dimensionseffective to permit soft tissue to grow therein.
 11. Method of claim 10wherein said pores comprise up to about 60 percent of said material. 12.Method of claim 11 wherein said pores comprise between about 40 andabout 60 percent of said material.
 13. Method of claim 10 wherein saidpores have a size of less than about 100 microns.
 14. Method of claim 13wherein said pores have a size of between about 50 and about 100microns.
 15. Method of claim 1 wherein said particles have an inner corecomprised of a first biologically-compatible polymeric material and anouter layer generally surrounding said inner core, said outer layercomprised of a second biologically-compatible polymeric material, saidsecond polymeric material being hydrophilic and having a compositiondifferent from the composition of said first polymeric material. 16.Method of claim 15 wherein said first polymeric material is an acrylicpolymer.
 17. Method of claim 16 wherein said first polymeric material ispolymethylmethacrylate.
 18. Method of claim 15 wherein said secondpolymeric material is a polymeric hydroxyethylmethacrylate.
 19. Methodof claim 18 wherein said polymeric hydroxyethylmethacrylate comprises acopolymer of monomeric hydroxyethylmethacrylate and a cross-linkingagent.
 20. Method of claim 1 wherein the step of providing abiologically compatible implant material further comprises combiningsaid particles with a matrix material.
 21. Method of claim 20 whereinsaid matrix material comprises a volume of between about 30% and about65% of the volume of said implant material.
 22. Method of claim 21wherein said matrix material comprises a volume of about 50% of thevolume of said implant material.
 23. Method of claim 20 wherein saidmatrix material is selected from the group consisting of sterile water,saline solution, adipose tissue, blood, glucose, hyaluronic acid, andcollagen.
 24. Method of claim 23 wherein said matrix material comprisescollagen.
 25. Method of claim 24 wherein said collagen comprisesinjectable collagen.
 26. Method of claim 1 wherein the step of providinga biologically compatible implant material further comprises the step ofcombining said particles with at least one bioactive substance. 27.Method of claim 26 wherein the combining step includes grafting said atleast one bioactive substance to said particles.
 28. Method of claim 1,wherein said implanting step comprises implanting said implant materialin particulate form.
 29. Method of claim 1, wherein said polymericparticles are non-resorbable.
 30. A method of augmenting soft tissuecomprising: a. providing a biologically compatible implant materialcomprising particles having an inner core comprised ofpolymethylmethacrylate and an outer layer generally surrounding saidinner core comprised of polymeric hydroxyethylmethacrylate, saidparticles having interstices therebetween with dimensions effective topermit soft tissue to grow therein; and b. implanting said implantmaterial within soft tissue in particulate form.
 31. Method of claim 30wherein said implanting step includes the step of injecting said implantmaterial.
 32. Method of claim 31 wherein said injecting step includesinjecting said implant material subcutaneously into an area having asoft tissue contour defect in an amount sufficient to at least partiallyremove said defect.
 33. Method of claim 32 wherein said soft tissuecontour defect comprises wrinkles.
 34. Method of claim 32 wherein saidsoft tissue contour defect includes gingival soft tissue defects in themouth.
 35. Method of claim 31 wherein said injecting step includesinjecting said material into the sphincter surrounding the urethra in anamount sufficient to at least partially constrict said urethra. 36.Method of claim 35 wherein said injecting step includes injectingbetween about 2 cc and about 4 cc of said implant material.
 37. Methodof claim 30 wherein said particles have a diameter of up to about 500microns.
 38. Method of claim 37 wherein said particles have a diameterof about 50 to about 200 microns.
 39. Method of claim 30 wherein saidparticles have intraparticulate pores, said pores having dimensionseffective to permit soft tissue to grow therein.
 40. Method of claim 30,wherein said particles have an amount of calcium hydroxide thereoneffective to induce soft tissue growth.
 41. Method of claim 40 whereinsaid pores comprise up to about 60 percent of said material.
 42. Methodof claim 41 wherein said pores comprise between about 40 and about 60percent of said material.
 43. Method of claim 40 wherein said pores havea size of less than about 100 microns.
 44. Method of claim 43 whereinsaid pores have a size of between about 50 and about 100 microns. 45.Method of claim 30 wherein the step of providing a biologicallycompatible implant material further comprises combining said particleswith a matrix material.
 46. Method of claim 45 wherein said matrixmaterial comprises a volume of between about 30% and about 65% of thevolume of said implant material.
 47. Method of claim 45 wherein saidmatrix material comprises a volume of about 50% of the volume of saidimplant material.
 48. Method of claim 45 wherein said matrix material isselected from the group consisting of sterile water, saline solution,adipose tissue, blood, glucose, hyaluronic acid, and collagen. 49.Method of claim 48 wherein said matrix material comprises collagen. 50.Method of claim 49 wherein said collagen comprises injectable collagen.51. Method of claim 30 wherein the step of providing a biologicallycompatible implant material further comprises the step of combining saidparticles with at least one bioactive substance.
 52. Method of claim 51wherein the combining step includes grafting said at least one bioactivesubstance to said particles.